Lymphoma is a cancer of lymphocytes. There are two main types of lymphoma: Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL). Non-Hodgkin lymphoma (NHL) is the most common type of lymphoma. Although there are more than 30 types of NHL, diffuse large B-cell lymphoma (DLBCL) is the most common type, making up about 30 percent of all lymphomas. In the United States, DLBCL affects about 7 out of 100,000 people each year.
Diffuse large B-cell lymphoma is an aggressive lymphoma, sometimes termed as a high or intermediate grade lymphoma. That means that the lymphoma grows quickly, and can spread fast to different parts of the body. Diffuse large B-cell lymphoma mostly affects those above 50 years of age, though people of any age can get it. It is a bit more common in men than in women. About ⅔ of those who have diffuse large B-cell lymphoma have widespread disease at the time of diagnosis, extending to different parts of the body. In nearly half of the patients, the disease affects parts of the body outside the lymph nodes (called “extranodal” disease). The bone marrow is affected in about 10-20% of the patients. DLBCL is fatal if left untreated.
In DLBCL, the abnormal B-cell lymphocytes are larger than normal, and they have stopped responding to signals that usually limit the growth and reproduction of cells. DLBCL can either develop as a transformation from a less aggressive form of lymphoma or as a first occurrence of lymphoma (called de novo).
The first sign of DLBCL is often a quickly growing, non-painful mass in a lymph node in the neck, groin, or abdomen. Patients may also experience fever, weight loss, drenching night sweats, or other symptoms. In about 40 percent of cases, the cancer does not begin in the lymph nodes, but instead develops elsewhere. This is called extranodal disease. The most common site of extranodal involvement is the stomach or gastrointestinal tract, but the disease can arise in virtually any tissue. Most patients (about 60 percent) are not diagnosed with DLBCL until the disease is advanced (stage III or IV). In the remaining 40 percent of patients, the disease is confined to one side of the diaphragm (above or below the diaphragm). This is called localized disease.
Typically, the diagnosis of lymphoma is generally done with a lymph node biopsy. Once the diagnosis is confirmed, additional tests are performed to obtain more information about the extent to which the disease has spread in the body. This process is called staging. The results of these tests will help determine the most effective course of treatment.
The discussion of management of patients with diffuse large B-cell lymphoma can be conveniently divided into 3 groups: those presenting with localized disease, those presenting with disseminated disease, and those patients whose lymphoma recurs after an initial remission.
The standard treatment of advanced was and still is chemotherapy based on CHOP. CHOP consists of four chemotherapy drugs—Cyclophosphamide (also called Cytoxan/Neosar), Doxorubicin (also called Hydroxydaunorubicin) (or Adriamycin), Vincristine (Oncovin) and Prednisolone.
However, though the CHOP treatment was and is usually applied, the development of new treatment regimens including M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), MACOP-B (methotrexate with leucovorin rescue doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) and ProMACE/CytaBOM (cyclophosphamide, doxorubicin, etoposide cytozar, bleomycin, vincristine, methotrexate prednisone) were reported to achieve results that seemed much better than had been observed with CHOP. These so-called third-generation regimens appeared to represent an important advance in therapy until an intergroup trial carried out in the United States demonstrated no superiority over CHOP.
Nevertheless, the CHOP therapy was expanded to a combination of chemotherapy and immunotherapy, i.e. R-CHOP. R-CHOP is a combination of drugs used in chemotherapy for aggressive Non-Hodgkin Lymphomas (NHL). It adds the drug Rituximab—a monoclonal antibody against CD20, to the standard combination called CHOP.
A commonly applied R-CHOP treatment regime is as follows: Rituximab is administered as an infusion over a few hours on the first day of treatment, while the drugs of the CHOP regimen may be started the next day. The entire course is usually repeated every three weeks for 6-8 cycles. The first three drugs of the CHOP chemotherapy regimen are usually given as injections or infusions in veins on a single day, while prednisolone is taken as pills for five days. Each cycle is repeated every 3 weeks for 6-8 cycles. CHOP chemotherapy is used for many of the common types of aggressive Non-Hodgkin Lymphomas including Diffuse Large B-Cell Lymphoma (DLBCL). Nowadays, R-CHOP can be considered the standard first line treatment for patients with DLBCL.
DHAP is a further combination of chemotherapeutic agents that is sometimes applied for the treatment of DLBCL. The DHAP chemotherapeutics include: Dexamethasone, cytarabine, which is sometimes called Ara-C and cisplatin, which contains platinum. DHAP can also be combined with Rituximab (tradename Rituxan®), i.e., R-DHAP.
ICE is another combination of chemotherapeutic agents that is sometimes applied for the treatment of DLBCL and named after the initials of the chemotherapy drugs used, which are: Ifosfamide, Carboplatin, and Etoposide. R-ICE also includes the monoclonal antibody drug Rituximab.
However, despite this major therapeutic advance, a significant proportion of patients will relapse or remain refractory to initial chemoimmunotherapy. Accordingly, there is a need for alternative and/or adjuvant therapies for the treatment of the aggressive and fast growing bulky tumor mass caused by DLBCL. Accordingly, the technical problem of the present invention is to comply with this need.